Telomere biology disorders

Kam, Michelle; Nguyen, Trang; Ngeow, Joanne

doi:10.1038/s41525-021-00198-5

Cited by 41 publications

(40 citation statements)

References 99 publications

(239 reference statements)

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“…Only one patient (P3) did not have abnormal blood counts, and thus no further marrow analysis was needed. Similar to other manifestations of TBD/STS reported in the literature, 37 it is possible that this patient’s disease had slow progression in the hematopoietic system while resulting in premature aging in the lungs manifesting as pulmonary fibrosis.…”

Section: Discussionsupporting

confidence: 78%

Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue

Sharma

Sahoo

Honda

et al. 2022

Blood

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Human telomere biology disorders (TBD)/short telomere syndromes (STS) are heterogeneous disorders caused by inherited loss-of-function mutations in telomere-associated genes. Here, we identify three germline heterozygous missense variants in RPA1 gene in four unrelated probands presenting with short telomeres and varying clinical features of TBD/STS including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations. All variants cluster to DNA binding domain A of RPA1 protein. RPA1 is a single-strand DNA-binding protein required for DNA replication and repair and involved in telomere maintenance. We showed that RPA1E240K and RPA1V227A proteins exhibit increased binding to single-strand and telomeric DNA, implying a gain in DNA-binding function while RPA1T270A has binding properties similar to wild type protein. To study the mutational effect in a cellular system, we used CRISPR/Cas9 to knock-in the RPA1E240K mutation into healthy inducible pluripotent stem cells. This resulted in severe telomere shortening and impaired hematopoietic differentiation. Furthermore, in patient with RPA1E240K, we discovered somatic genetic rescue (SGR) in hematopoietic cells due to an acquired truncating cis RPA1 mutation or a uniparental isodisomy 17p with loss of mutant allele, coinciding with stabilized blood counts. Using single-cell sequencing, the two SGR events were proven to be independently acquired in hematopoietic stem cells. In summary, we describe the first human disease caused by germline RPA1 variants in individuals with TBD/STS.

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Section: Discussionsupporting

confidence: 78%

Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue

Sharma

Sahoo

Honda

et al. 2022

Blood

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“…In a recent publication, approximately 18 of 180 patients with a TBD were diagnosed with AML or MDS ( 23 ). Other hematologic conditions have been described, such as macrocytosis, isolated cytopenias, paroxysmal nocturnal hemoglobinuria and essential thrombocythemia ( 24 ).…”

Section: Telomere Biology Disordersmentioning

confidence: 99%

Non-Melanoma Skin Cancers and Other Cutaneous Manifestations in Bone Marrow Failure Syndromes and Rare DNA Repair Disorders

et al. 2022

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Although most non-melanoma skin cancers are felt to be sporadic in origin, these tumors do play a role in several cancer predisposition syndromes. The manifestations of skin cancers in these hereditary populations can include diagnosis at extremely early ages and/or multiple primary cancers, as well as tumors at less common sites. Awareness of baseline skin cancer risks for these individuals is important, particularly in the setting of treatments that may compromise the immune system and further increase risk of cutaneous malignancies. Additionally, diagnosis of these disorders and management of non-cutaneous manifestations of these diseases have profound implications for both the patient and their family. This review highlights the current literature on the diagnosis, features, and non-melanoma skin cancer risks associated with lesser-known cancer predisposition syndromes, including bone marrow failure disorders, genomic instability disorders, and base excision repair disorders.

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“…DC-linked mutations in telomere genes include those of DKC1, TINF2, NOP10, NHP2, TCAB1, and CTC1 (6). IPF is the most common manifestation of other adult TBDs (21). It is not surprising that more than one TBD or clinical presentation can be observed in the same patient or family, but usually, one disease is predominant (6,21,22).…”

Section: Telomere Biology Disorders and Chronic Lung Diseasesmentioning

confidence: 99%

“…IPF is the most common manifestation of other adult TBDs (21). It is not surprising that more than one TBD or clinical presentation can be observed in the same patient or family, but usually, one disease is predominant (6,21,22). This might be caused by germline telomere gene mutations that can affect the homeostasis of multiple organ systems.…”

Section: Telomere Biology Disorders and Chronic Lung Diseasesmentioning

confidence: 99%

“…Telomere biology disorders are a heterogeneous phenotypic group of illnesses arising from germline mutations that affect telomere maintenance ( 21 ). The first telomere biology disorder (TBD) was described as dyskeratosis congenita (DC), a hereditary disorder seen in childhood, in which ~20% of DC patients develop pulmonary fibrosis in later life ( 21 ). DC-linked mutations in telomere genes include those of DKC1, TINF2, NOP10, NHP2, TCAB1 , and CTC1 ( 6 ).…”

Section: Telomere Biology Disorders and Chronic Lung Diseasesmentioning

confidence: 99%

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Telomere Dysfunction in Idiopathic Pulmonary Fibrosis

Zhang

Cong

2021

Front. Med.

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Idiopathic pulmonary fibrosis is an age-dependent progressive and fatal lung disease of unknown etiology, which is characterized by the excessive accumulation of extracellular matrix inside the interstitial layer of the lung parenchyma that leads to abnormal scar architecture and compromised lung function capacity. Recent genetic studies have attributed the pathological genes or genetic mutations associated with familial idiopathic pulmonary fibrosis (IPF) and sporadic IPF to telomere-related components, suggesting that telomere dysfunction is an important determinant of this disease. In this study, we summarized recent advances in our understanding of how telomere dysfunction drives IPF genesis. We highlighted the key role of alveolar stem cell dysfunction caused by telomere shortening or telomere uncapping, which bridged the gap between telomere abnormalities and fibrotic lung pathology. We emphasized that senescence-associated secretory phenotypes, innate immune cell infiltration, and/or inflammation downstream of lung stem cell dysfunction influenced the native microenvironment and local cell signals, including increased transforming growth factor-beta (TGF-β) signaling in the lung, to induce pro-fibrotic conditions. In addition, the failed regeneration of new alveoli due to alveolar stem cell dysfunction might expose lung cells to elevated mechanical tension, which could activate the TGF-β signaling loop to promote the fibrotic process, especially in a periphery-to-center pattern as seen in IPF patients. Understanding the telomere-related molecular and pathophysiological mechanisms of IPF would provide new insights into IPF etiology and therapeutic strategies for this fatal disease.

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Telomere biology disorders

Cited by 41 publications

References 99 publications

Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue

Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue

Non-Melanoma Skin Cancers and Other Cutaneous Manifestations in Bone Marrow Failure Syndromes and Rare DNA Repair Disorders

Telomere Dysfunction in Idiopathic Pulmonary Fibrosis

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